LEHNINGER PRINCIPLES OF BIOCHEMISTRY - VOL. 2. BIOENERGETICS AND METABOLISM - 2014

PART II. BIOENERGETICS AND METABOLISM

Class="center">I chose to study urea synthesis in the Liver because it seemed to me to be a relatively simple problem.

Hans Krebs, from Perspectives in Biology and Medicine, 1970

18. OXIDATIVE DEGRADATION OF AMINO ACIDS AND THE UREA CYCLE

We now turn to Amino Acids, the final class of Biomolecules from which organisms can derive significant amounts of energy through oxidative degradation. The energetic contribution of amino acids—whether from dietary Proteins or tissue proteins—varies widely depending on the type and metabolic state of the Organism. Carnivores can derive up to 90% of their Energy Requirements immediately after a meal through amino acid oxidation, whereas herbivores utilize only a small fraction of their energy in this manner. Many microorganisms can scavenge even trace amounts of amino acids from their environment and use them as fuel under specific nutritional conditions. Plants, by contrast, very rarely oxidize amino acids for energy; their primary energy source consists of CARBOHYDRATES produced from CO₂ and H₂O during Photosynthesis. The concentration of amino acids in plant Tissues is tightly regulated to maintain the proper balance of rates for the Biosynthesis of Proteins, Nucleic Acids, and other molecules required for growth. Thus, Amino Acid Catabolism does occur in plants, but primarily to supply metabolites for other biosynthetic pathways.

In animal Cells, amino acids undergo oxidative degradation in three principal circumstances:

1. During the normal Synthesis and degradation of cellular proteins (protein turnover, Chapter 27, Vol. 3). When amino acids released from protein breakdown are not needed for the synthesis of new proteins, they undergo oxidative degradation.

2. When a diet is rich in proteins, the intake of amino acids exceeds the body's requirements for Protein Synthesis, and the surplus enters Catabolic pathways. Amino acids cannot be stored.

3. During starvation or in uncontrolled Diabetes Mellitus, when carbohydrates are either unavailable or cannot be utilized as fuel, cellular proteins are called upon for energy.

In all these situations, amino acids lose their amino groups to yield α-ketoacids—the carbon skeletons of the amino acids. These α-ketoacids are oxidized to CO₂ and H₂O or, more importantly, converted into three- or four-carbon units that can enter Gluconeogenesis to yield glucose, ensuring a continuous energy supply for the Brain, skeletal Muscles, and other tissues.

The catabolic PATHWAYS OF AMINO acids are remarkably similar across most organisms. This chapter focuses primarily on the Metabolic pathways of vertebrates, as they are the most thoroughly characterized. Much like The breakdown of carbohydrates and Fatty acids, the degradation pathways of amino acids ultimately converge on central catabolic pathways, wherein the carbon skeletons of Most amino acids enter The Citric Acid Cycle. Furthermore, several reactions in amino acid degradation closely parallel those of Fatty acid oxidation (Chapter 17).

What distinguishes Amino Acid Breakdown from the other catabolic processes discussed thus far is a crucial feature: every amino acid contains an amino group. Consequently, their degradation pathways include a key initial step in which the α-amino group is separated from the carbon Skeleton and channeled into Amino Group METABOLISM (Fig. 18-1). We will first examine the metabolism of amino groups and The excretion of nitrogen, followed by The Fate of the remaining carbon skeletons, and see how these pathways intersect.

Fig. 18-1 Overview of amino acid catabolism in mammals. Amino groups and carbon skeletons are metabolized via separate yet intersecting pathways.

18.1. Metabolic Pathways of Amino Groups

Although molecular nitrogen (N₂) is the most abundant gas in the atmosphere, it is far too inert to participate in most biochemical processes. Because only a few microorganisms are capable of converting N₂ into biologically useful forms such as NH₃ (Chapter 22), Amino groups are carefully conserved in biological systems.

Figure 18-2a provides An Overview of the catabolic pathways for ammonia and amino groups in vertebrates. The primary source of amino groups is dietary protein. Most Amino acids are metabolized in the liver. The ammonia generated in this process is reassimilated and utilized in various biosynthetic pathways; excess ammonia is either excreted directly or converted into urea or uric acid prior to excretion, depending on the

organism (Fig. 18-2b). Excess ammonia produced in extrahepatic (non-hepatic) tissues is transported to the liver—carried as amino groups, as described below—to be converted into an excretable form.

Fig. 18-2 Catabolism of amino groups. (a) Overview of amino group catabolism in the vertebrate liver. (b) Excretory forms of nitrogen. Excess NH+4 is excreted as ammonium (microbes, teleost fish), urea (most terrestrial vertebrates), or uric acid (Birds and terrestrial reptiles). Note that the carbon in urea and uric acid is in its most oxidized state; organisms excrete carbon only after extracting the maximum possible amount of energy from its oxidation.

Glutamate and glutamine play exceptionally pivotal roles in Nitrogen metabolism by acting as the principal collectors of amino groups. In the hepatocyte Cytosol, the amino groups of most amino acids are transferred to α-ketoglutarate to yield glutamate, which then enters the Cell/35.html">Mitochondria. Inside the mitochondrial matrix, these amino groups are released as NH⁺₄. Excess ammonia generated in most other tissues is converted into the amide nitrogen of glutamine, which travels to The Liver and subsequently into liver mitochondria. In nearly all tissues, the concentrations of glutamine and/or glutamate are significantly higher than those of Other Amino Acids.

In Skeletal Muscle, excess amino groups are transferred primarily to Pyruvate to form Alanine, which likewise participates in the Transport of Amino groups to the liver.

We will begin our Structure/133.html">Discussion with the breakdown of dietary proteins, followed by a General Overview of the metabolic pathways of amino groups.

Dietary proteins undergo enzymatic breakdown to amino acids

In The Human Body, the breakdown of dietary proteins into amino acids occurs within the gastrointestinal tract. The entry of food proteins into The Stomach stimulates the gastric mucosa to secrete the hormone gastrin, which in turn stimulates parietal cells to secrete Hydrochloric acid and chief Cells of the gastric glands to secrete pepsinogen (Fig. 18-3a). Acidic gastric juice (pH 1.0 to 2.5) Functions both as an antiseptic—killing most Bacteria and other foreign cells—and as a denaturing agent that unravels Globular proteins, rendering their internal peptide bonds more accessible to Enzymatic Hydrolysis. The inactive precursor pepsinogen (Mr 40,554), or zymogen (p. 328, vol. 1), is converted into active Pepsin (Mr 34,614) via autocatalytic Cleavage (the enzymatic action of pepsin itself), which is triggered only when the pH drops. In the stomach, pepsin hydrolyzes ingested proteins at peptide bonds on the amino-terminal side of aromatic amino acid residues Phe, Trp, and Tyr (see Table 3-7, vol. 1), cleaving long polypeptide chains into a mixture of smaller Peptides.

As the acidic stomach contents pass into the Small Intestine, the low pH triggers the release of the hormone secretin into the bloodstream by the duodenal mucosa. Secretin stimulates the Pancreas to secrete bicarbonate into the small intestine to neutralize HCl, causing a sharp rise in pH to approximately 7. (All pancreatic secretions enter the small intestine via the pancreatic duct.) Protein Digestion now proceeds with lower intensity. The entry of amino acids into the upper region of the intestine (the duodenum) prompts the release of the hormone cholecystokinin into the Blood, which stimulates the secretion of several pancreatic Enzymes with an optimum pH of ~7–8. Trypsinogen, chymotrypsinogen, and procarboxypeptidases A and B, the zymogens of Trypsin, Chymotrypsin, and Carboxypeptidases A and B, are synthesized and secreted by the exocrine cells of the pancreas (Fig. 18-3b). Under the action of enteropeptidase, a proteolytic enzyme released by intestinal cells, trypsinogen is converted into its active form, trypsin, which then catalyzes The conversion of the remaining trypsinogen into trypsin (see Fig. 6-38, vol. 1). Trypsin also activates chymotrypsinogen, procarboxypeptidases, and proelastases.

Why is such a complex mechanism required to activate digestive enzymes in the gastrointestinal tract? Synthesizing enzymes as inactive precursors protects the exocrine cells from the destructive effects of their own proteolytic activity. Furthermore, the pancreas prevents self-digestion by secreting a specific inhibitor—the protein pancreatic trypsin inhibitor (p. 328, vol. 1)—which effectively prevents the premature formation of active Proteolytic Enzymes within the pancreatic cells.

Trypsin and chymotrypsin subsequently cleave the peptides produced in the stomach by the action of pepsin. This stage of protein digestion is carried out with high efficiency because pepsin, trypsin, and chymotrypsin exhibit different amino acid specificities (see Table 3-7, vol. 1). The breakdown of short peptides in the small intestine is completed by other intestinal peptidases, including carboxypeptidases A and B (zinc-containing enzymes) that sequentially remove amino acid residues from the C-terminus of the peptide, and aminopeptidases that sequentially remove amino acid residues from the N-terminus. The mixture of free amino acids is transported into the epithelial cells lining the small intestine (Fig. 18-3c), through which they enter the blood capillaries of the villi and are transported to the liver. In humans, globular proteins from animal foods are almost completely hydrolyzed to amino acids within the gastrointestinal tract, whereas certain Fibrous proteins, such as keratin, are only partially digested. The protein content of cells in some plant foods is protected from degradation by indigestible Cellulose coats.

Fig. 18-3. The Human digestive tract. (a) Parietal and chief cells of the gastric glands secrete their products in response to the hormone gastrin. Protein digestion begins in the stomach via pepsin. (b) The Cytoplasm of exocrine cells is packed with rough Endoplasmic reticulum, the site of synthesis for zymogens (proenzymes) of numerous digestive enzymes. The zymogens are housed in membrane-bound transport vesicles known as zymogen granules. Upon stimulation of an exocrine cell, its Plasma Membrane fuses with the membranes of the zymogen granules, releasing the zymogens into the lumina of collecting ducts via exocytosis. The collecting ducts lead to the pancreatic duct and thence to the small intestine. (c) Amino acids are absorbed by the epithelial cells (intestinal mucosa) of the villi and enter the capillaries. Recall that lipid hydrolysis products in the small intestine, following absorption by the intestinal mucosa, enter The Lymphatic system (see Fig. 17-1).

In acute pancreatitis, normal digestion is disrupted, specifically due to the impaired delivery of pancreatic secretions into the intestine. Zymogens of proteolytic enzymes are converted into catalytically active forms prematurely, inside the pancreatic cells, and attack the pancreas itself. This causes excruciating pain and organ destruction, which can have fatal consequences. ■

Pyridoxal phosphate participates in The transfer of an α-amino group to α-ketoglutarate

Catabolism of most L-amino acids in the liver begins with the removal of the α-amino group, carried out by enzymes known as aminotransferases or transaminases. In these Transamination reactions, the α-amino group is transferred to the α-carbon atom of α-ketoglutarate, resulting in an α-keto acid, the analogue of The amino acid (Fig. 18-4). There is no net deamination (loss of the amino group) here, because α-ketoglutarate acquires an amino group while the α-amino acid loses one. As a result of transamination reactions, the amino groups from many different amino acids are collected in the form of L-glutamate. Glutamate then functions as an amino group donor for biosynthetic pathways or for excretory pathways that lead to the removal of nitrogenous waste products.

Fig. 18-4. Enzymatic transamination. In most aminotransferase reactions, the amino group acceptor is α-ketoglutarate. All aminotransferases use pyridoxal phosphate (PLP) as a cofactor. Although the reaction is shown here in the direction of amino group transfer to α-ketoglutarate, it is readily reversible.

Cells contain various types of aminotransferases. Many of these are specific for α-ketoglutarate as the amino group acceptor, but differ in their Specificity for α-amino acids. The Reactions Catalyzed by aminotransferases are readily reversible; the Equilibrium Constant is ~ 1.0 (∆G' ≈ 0 kJ/mol).

All aminotransferases share the same prosthetic group and reaction mechanism. This prosthetic group is pyridoxal phosphate (PLP), the coenzyme form of pyridoxine, or vitamin B₆. We introduced pyridoxal phosphate in Chapter 15 as a coenzyme for Glycogen phosphorylase, though the role PLP plays in that reaction is somewhat atypical. Its primary cellular function is to participate in the metabolism of amino-group-containing molecules.

Pyridoxal phosphate functions as an intermediate carrier of amino groups at the Active Site of aminotransferases. It reversibly interconverts between its aldehyde form—pyridoxal phosphate, which can accept amino groups—and its aminated form—pyridoxamine phosphate, which can donate amino groups to an α-keto acid (Fig. 18-5a). Pyridoxal phosphate is typically covalently bound to the enzyme's active site, forming a Schiff base with the ε-amino group of a Lys residue (Fig. 18-5b, d).

Fig. 18-5. Pyridoxal phosphate as the prosthetic group of aminotransferases. (a) Pyridoxal phosphate (PLP) and its amino derivative, pyridoxamine phosphate, are tightly bound Coenzymes of aminotransferases, with functional groups highlighted in pink. (b) Pyridoxal phosphate is linked to the enzyme through noncovalent interactions and forms a Schiff base via an active-site Lys residue. The formation of a Schiff base from a primary amine and a carbonyl group is detailed in Figure 14-5. (c) The PLP molecule (red) is bound to one of the two active sites of the aspartate aminotransferase dimer, a typical aminotransferase. (d) Active site containing PLP (shown in red with a yellow phosphate group) forming an aldimine linkage with the side chain of Lys²⁵⁸ (purple). (e) Active site with PLP bound to the substrate analog 2-methylaspartate (green) via a Schiff base (PDB ID 1AJS).

Pyridoxal phosphate participates in a diverse array of Reactions Involving the α-, β-, and γ-carbons of amino acids (C-2 through C-4). Alongside transamination reactions, the α-carbon of amino acids (Fig. 18-6) can undergo racemization (the interconversion of L- and D-amino acids) and decarboxylation. PLP plays a consistent role across all these chemical pathways: the bond linking the substrate's α-carbon to either a proton or a carboxyl group is cleaved. The resulting electron pair leaves the α-carbon as a highly unstable carbanion, but PLP Resonance-stabilizes this intermediate (Fig. 18-6, inset). This conjugated structure of PLP (acting as an electron sink) facilitates the delocalization of the negative charge.

Fig. 18-6. Reaction mechanism. Selected transformations at the α-carbon of amino acids involving pyridoxal phosphate. PLP is typically bound to the enzyme via a Schiff base, also referred to as an internal aldimine. This activated form of PLP undergoes immediate transamination to form a new Schiff base (a standard aldimine) with the α-amino group of the incoming amino acid substrate (see Fig. 18-5b, d). Three alternative fates for this Schiff base are shown: (A) transamination, (B) racemization, and (C) decarboxylation. The Schiff base formed between PLP and the amino acid is conjugated with the pyridine ring, which acts as an electron sink to delocalize electron density and prevent the formation of an unstable carbanion with charge localized on the α-carbon (inset). A quinonoid intermediate is common to all three reactions. The transamination reaction (A) is particularly central to the pathway discussed in this chapter, highlighted here from left to right on the shaded Background; these represent only a subset of aminotransferase-catalyzed reactions. In the complete physiological process, a second α-keto acid replaces the amino acid released in the reverse reaction (right to left). PLP also participates in the β- and γ-carbon reactions of Certain amino acids (not shown).

Aminotransferases (Fig. 18-5) are classic Examples of enzymes that catalyze bimolecular reactions via a ping-pong mechanism (see Fig. 6-13b). In such reactions, the first product leaves the active site before the second substrate binds. Thus, the incoming amino acid binds to the active site, transfers its amino group to pyridoxal phosphate, and departs as an α-keto acid. Subsequently, the incoming α-keto acid binds, accepts the amino group from pyridoxamine phosphate, and is released as an amino acid. As discussed in Box 18-1, measuring serum alanine and aspartate aminotransferase levels provides critical diagnostic information for various clinical conditions.

Box 18-1. MEDICINE. Diagnostic Value of Evaluating Damage to Human Organs

Assays of blood serum for specific enzymatic activities provide valuable diagnostic insights into a range of diseases.

The levels of alanine aminotransferase (commonly abbreviated as ALT, also known as glutamate-pyruvate transaminase, GPT) and aspartate aminotransferase (AST, also known as glutamate-oxaloacetate transaminase, GOT) serve as important clinical markers for detecting Heart and liver cell damage resulting from myocardial infarction, drug toxicity, or infection. Following a myocardial infarction, various enzymes, including these aminotransferases, leak from damaged cardiac muscle cells into the bloodstream. Measuring the serum concentrations of these two aminotransferases (historically referred to as SGPT and SGOT, where 'S' stands for serum), along with the enzyme creatine kinase (CK), helps determine the time elapsed since the myocardial injury. Creatine kinase appears in the blood more rapidly than Other Enzymes following a heart attack, but it clears relatively quickly. Elevations in GOT follow CK, which are subsequently followed by elevations in GPT. Lactate dehydrogenase is also released from damaged anaerobic heart muscle cells.

SGOT and SGPT assays are similarly valuable during routine occupational health screenings to detect liver damage in workers handling carbon tetrachloride, chloroform, or other industrial Solvents. Poisoning by these compounds triggers the leakage of various enzymes from damaged hepatocytes into the blood. Workers exposed to these chemicals are routinely monitored for elevated aminotransferase levels; because these enzyme activities are exceptionally high in the liver, even minor hepatocellular injury can be readily detected.

In the Liver, the Amino Group of Glutamate is Released as Ammonia

As we discussed earlier, the amino groups of most amino acids are collected in the liver as the amino groups of L-glutamate. To clear these amino groups from the body, they must be removed from glutamate. In hepatocytes, glutamate is transported from the cytosol into the mitochondria, where it undergoes Oxidative Deamination catalyzed by L-Glutamate dehydrogenase (Mr 330,000). In mammals, this enzyme is located in the mitochondrial matrix. It is the unique enzyme capable of using either NAD⁺ or NADP⁺ as a substrate for the generation of reducing equivalents (Fig. 18-7).

Fig. 18-7. The reaction catalyzed by glutamate dehydrogenase. Mammalian liver glutamate dehydrogenase has the unusual ability to use either NAD⁺ or NADP⁺ as a cofactor. Plant or microbial glutamate dehydrogenases are typically specific for a single cofactor. The mammalian enzyme is allosterically regulated by GTP and ATP.

The combined action of aminotransferase and glutamate dehydrogenase is termed transdeamination. Some amino acids bypass the transamination step and undergo oxidative deamination directly. The fate of NH₄⁺ generated during deamination processes is discussed in detail in Section 18.2. The α-ketoglutarate produced from glutamate deamination can enter The Citric Acid cycle or be utilized in glucose synthesis.

Glutamate dehydrogenase operates at a metabolic crossroads between carbon and nitrogen metabolism. This enzyme consists of six identical subunits, and its activity is governed by a complex array of allosteric modulators. Among these, the positive modulator (activator) ATP and the negative modulator (inhibitor) GTP are the most extensively studied. The precise physiological rationale for this regulatory mechanism is not yet fully understood. Mutations that alter the allosteric GTP-binding site or otherwise cause constitutive activation of glutamate dehydrogenase lead to a human genetic disorder known as hyperinsulinism-hyperammonemia syndrome, which is characterized by elevated blood ammonium levels and hypoglycemia.

Ammonia is transported in the Bloodstream as Glutamine

Ammonia is highly toxic to animal tissues (we will examine several probable causes of this later), and its blood concentration is tightly regulated. In virtually all tissues, including the brain, processes such as nucleotide breakdown release ammonia. In most animals, nearly all free ammonia is converted into a nontoxic compound before it is exported from extrahepatic tissues into the blood for transport to the liver or Kidneys. To fulfill this transport function, glutamate—which plays a pivotal role in intracellular amino group metabolism—is converted into L-glutamine. Free ammonia released by tissues combines with glutamate to form glutamine through the action of Glutamine Synthetase. This reaction proceeds in two steps, driven by the energy of ATP hydrolysis (Fig. 18-8). First, glutamate and ATP react to form ADP and a γ-glutamyl phosphate intermediate, which subsequently reacts with ammonia to yield glutamine and inorganic phosphate. Glutamine serves as a nontoxic transport vehicle for ammonia; under normal conditions, its concentration in the blood exceeds that of any other amino acid. Glutamine also functions as an amino group donor in various biosynthetic reactions. Glutamine synthetase is found in all organisms and invariably occupies a central metabolic role. In microorganisms, this enzyme assimilates a substantial portion of fixed nitrogen into biological molecules. (The roles of glutamine and glutamate synthetases in metabolism are discussed in Chapter 22.)

Fig. 18-8. Ammonium is transported in the form of glutamine. Excess ammonium in tissues is added to glutamate to form glutamine in a reaction catalyzed by glutamine synthetase. Through the bloodstream, glutamine reaches the liver, where NH⁺₄ is released by the enzyme glutaminase.

In most terrestrial animals, excess glutamine not required for biosynthesis is transported via the bloodstream to the intestine, liver, and kidneys for Processing. There, the amide nitrogen is released as an ammonium ion within the mitochondria, where the enzyme glutaminase converts glutamine into glutamate and NH⁺₄ (Fig. 18-8). Ammonium from the intestine and kidneys is then carried via the bloodstream to the liver, where the incoming NH⁺ participates in urea synthesis. A portion of the glutamate generated by the glutaminase reaction may subsequently be acted upon by liver glutamate dehydrogenase to yield additional ammonium along with carbon skeletons for fuel storage molecules. However, the bulk of glutamate enters transamination pathways for Amino acid biosynthesis and other reactions (Chapter 22). During metabolic acidosis (p. 254), renal glutamine processing is upregulated. As a result, not all excess existing NH⁺₄ is released into the blood or converted into urea; a fraction is excreted directly into the urine. In the kidneys, it forms salts with metabolic acids, facilitating their elimination in the urine. Bicarbonate ions generated by the decarboxylation of α-ketoglutarate in the citric acid cycle can also act as Blood Plasma buffers. Together, these renal glutamine metabolic pathways help counteract acidosis. ■

Alanine Transports Ammonia from Skeletal Muscle to the Liver

Alanine also plays a crucial role in transporting amino groups in a nontoxic form to the liver via a pathway known as the glucose-alanine cycle (Fig. 18-9). In muscles and certain other tissues where amino acid degradation occurs for energy generation, amino groups are funneled into glutamate via transamination (Fig. 18-2a). Glutamate can either be converted into glutamine for delivery to the liver, as described above, or transfer its α-amino group to pyruvate—readily available from muscle Glycolysis (Fig. 18-9)—via the action of alanine aminotransferase. The alanine thus formed enters the bloodstream and is transported to the liver. In the hepatocyte cytosol, an aminotransferase transfers the amino group of alanine to α-ketoglutarate, yielding pyruvate and glutamate. Glutamate can then enter the mitochondria, where the glutamate dehydrogenase reaction releases NH⁺₄ (Fig. 18-7), or it can undergo transamination with oxaloacetate to form aspartate, another nitrogen donor for urea synthesis, as we will soon see.

Fig. 18-9. The glucose-alanine cycle. Alanine functions as a carrier of both ammonium and the pyruvate carbon skeleton from skeletal muscle to the liver. Ammonium is excreted, while pyruvate is utilized for glucose synthesis and subsequently returned to Muscle tissue.

The Use of alanine to ferry ammonia from skeletal muscle to the liver is yet another example of biological efficiency. Actively contracting skeletal muscle obtains energy anaerobically through glycolysis, producing pyruvate and lactate, while protein breakdown generates ammonia. These metabolic end products must travel to the liver, where pyruvate and lactate are converted back into glucose for return to the muscle, and ammonia is converted into urea for excretion. These transformations take place within the glucose-alanine cycle, operating in tandem with the Cori cycle (see Box 14-2 and Fig. 23-20). Consequently, the energetic burden of gluconeogenesis is largely assumed by the liver rather than the muscle, allowing all available muscle ATP to be dedicated to contraction.

Ammonia is toxic to Animals

The generation of ammonia during catabolic processes poses a major biochemical challenge because ammonia is highly toxic. The molecular mechanisms underlying this toxicity are not yet fully understood. In humans, the terminal stages of ammonia intoxication are characterized by coma, accompanied by cerebral edema and elevated intracranial pressure; consequently, investigations into the causes of ammonia toxicity are conducted primarily using brain tissue. According to one prevailing theory, severe ATP depletion in brain cells is considered the primary driver of ammonia toxicity.

Clearing excess ammonia from the cytosol requires the reductive amination of α-ketoglutarate to glutamate via glutamate dehydrogenase (the reverse of the reaction described earlier, Fig. 18-7) or the conversion of glutamate into glutamine via glutamine synthetase. Both enzymes are present in high concentrations in the brain, although the glutamine synthetase reaction almost certainly plays the more critical role in ammonia detoxification. High levels of NH⁺₄ lead to an accumulation of glutamine, an osmolite that is osmotically active within brain astrocytes—the glial cells that provide nutritional support, structural maintenance, and insulation for Neurons. This influx of osmolytes triggers Water uptake by astrocytes to maintain osmotic balance, resulting in cellular Swelling, cerebral edema, and ultimately coma.

Depletion of glutamate reserves due to the glutamine synthetase reaction may exert additional adverse effects on the brain. Glutamate and its derivative γ-aminobutyric acid (GABA) are vital Neurotransmitters; thus, the brain's acute sensitivity to ammonia, alongside disruptions in osmotic balance, may partly reflect a deficiency in neurotransmitter pools. ■

With this, we conclude our discussion of amino group metabolism. Note that we have outlined several pathways by which excess ammonia is delivered to hepatocyte mitochondria (Fig. 18-2). Next, we will examine the ultimate fate of this ammonia.

Summary of Section 18.1 Metabolic Pathways of Amino Groups

■ Humans derive a relatively small fraction of their energy from amino acid catabolism. Amino acids produced during the routine turnover of cellular proteins, the Digestion of dietary proteins, and the degradation of proteins serve as alternative Energy Sources during starvation or uncontrolled diabetes mellitus.

■ Proteases break down dietary proteins in the stomach and small intestine. Most of these proteases are initially synthesized as inactive zymogens.

■ The first step in amino acid catabolism involves the removal of the amino group from the carbon skeleton. In most cases, the amino group is transferred to α-ketoglutarate to yield glutamate. This transamination reaction requires pyridoxal phosphate.

■ Glutamate is transported into liver mitochondria, where glutamate dehydrogenase releases the amino group as an ammonium ion (NH⁺₄). Ammonia generated in extrahepatic tissues is delivered to the liver as the amide nitrogen of glutamine, whereas from skeletal muscles it is transported as the amino group of alanine.

■ Pyruvate formed during the deamination of alanine in the liver is converted into glucose, which is transported back to the muscles as part of the glucose-alanine cycle.